The invention relates to tapentadol for use in the treatment of pain in a subject suffering from pain chronification and/or for use in the treatment or the inhibition of pain chronification. The invention also relates to tapentadol for use in the treatment or inhibition of migraine, i.e. of migraine-related pain, and headache-related pain.
Tapentadol (CG5503), the chemical name for which is (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, is a synthetic, centrally-acting analgesic that is effective for the treatment of moderate to moderately-severe acute or chronic pain. The compound can be employed as the free base or its pharmaceutically acceptable salts and solvates. Preparation of the free base is known from EP-A 693 475.
Tapentadol is a centrally acting analgesic with a dual mode of action consisting of p-opioid receptor (MOR) agonism and norepinephrine (NE) reuptake inhibition. The efficacy, safety, and pharmacokinetic profile of tapentadol indicate that the drug is useful in treating acute as well as chronic pain. The mixed μ-opioid receptor agonist/noradrenaline reuptake inhibitor, tapentadol, was found to reduce acute and chronic pain in validated animal models. However none of these models involved pain at cephalic level.
The activity of tapentadol is independent of metabolic activation and resides in a single enantiomer which readily crosses the blood-brain barrier; hence, tapentadol displays a rapid onset of action after administration. The biotransformation of tapentadol by metabolic enzymes results in deactivation, i.e., tapentadol has no active metabolites, and the main metabolic pathway for elimination is phase II glucuronidation. Phase I biotransformations such as hydroxylation and N-demethylation play only a minor role in the metabolic fate of tapentadol. Owing to the minor involvement of phase I metabolic pathways, tapentadol has a low potential for drug-drug interactions and interindividual variability (cf. Tzschentke T. M. et al. Tapentadol Hydrochloride. Drugs of the Future 2006, 31, 1053-1061; Evans W. E., Relling, M. V. Pharmacogenomics: Translating Functional Genomics into Rational Therapies. Science 1999, 286, 487-491).
EP 1 985 292 relates to titration regimens of tapentadol. The official expert information concerning Palexia®, a commercial product containing tapentadol, indicates that tapentadol is for treating chronic pain. Rauschkolb-Loeffler et al., Annals of the rheumatic diseases, 2007, 507 relates to a clinical trial concerning treatment of chronic pain due to osteoarthritis of the knee.
Chronic pain due to chronification of pain, however, is not synonymous to chronic pain in general; not every chronic pain is a result of pain chronification. Instead, chronic pain due to chronification of pain is a sub-type of chronic pain. Chronification of pain is the conversion of acute pain into chronic pain. It is known that therapy of acute pain, e.g. postoperative pain (postsurgical pain), by means of conventional analgesics can result in chronification of pain. In consequence, pain sensation last longer than would typically be expected in view of progressing postoperative wound healing; even though wound healing has been nearly completed, the patient still suffers from pain. Chronification of pain can lead to e.g. persistent postsurgical pain (PPP), also referred to as chronic post-surgical pain (CPSP), which the International Association for the Study of Pain defined as a persistent pain state that is apparent for more than 2 months postoperatively and cannot be explained by other causes (recurrence of disease, inflammation, and others).
Chronic postoperative pain has estimated incidences of 30-50% after amputation, 20-30% after breast surgery, 30-40% after thoractomy, about 10% after inguinal hernia repair, 30-50% after coronary artery bypass surgery, and about 10% after Ceasarean section. Patients suffering from chronic pain are typically characterized by wide spread pain, a long lasting medical history, psycho-social problems as well as many unsuccessful treatments. For further details, it can be referred to e.g. W. A. Macrae, British Journal of Anaesthesia 101(1): 77-86 (2008); T. J. Brennan, Anesthesiology, 2010, 112:514-5; J. P. Rathmell et al., Anesthesiology, 2011, 114:1021-4; P. Lavand'homme, Curr Opin Anesthesiol 2011, 24:545-550; J. B. Dahl et al., Curr Opin Anesthesiol 2011, 24:331-338; E. A. Shipton, Anaesth Intensive Care 2011; 39, 824-836.
It is assumed that every nociceptive stimulus which acts on the central nervous system is capable of reinforcing pain in the long term thus leading to a chronification of pain. If corresponding stimuli are maintained for a prolonged time period, the synaptic transmission is amplified through a process called “long term potentiation,” resulting in pain chronification. Chronification processes are neuronal conduction processes caused by the plasticity of neuronal functions. The plasticity of neuronal functions allows for a mechanism called “wind up” in which subsequently incoming impulses are amplified. However, chronification of pain is not just a simple matter of duration. Chronification is more a spread of pain on the physical level, on duration and even more on the psychological and social levels. Evaluation of the amount of chronification may be based e.g. on the graduation of chronic pain by von Korff. Chronicity of pain correlates with quality of life and effectiveness of medical treatment.
On the one hand, mechanisms can be peripheral, i.e. primary afferent nociceptor sensitation, e.g., due to spontaneous activity, decreased threshold, increased response to suprathreshold stimulants, recruitment of silent nociceptors, and the like. On the other hand, mechanisms can also be central, i.e. central sensitization, e.g., due to enhanced synaptic excitability (dorsal root ganglia, dorsal horn), expansion of receptor fields, altered mood and autonomic reflexes in the limbic system and hypothalamus, activation of spinal circuits from brainstem, and the like.
As far as chronic post-surgical pain is concerned, many physicians believe that pain around the time of an operation sensitizes the nervous system and this hypersensitized state contributes to the development of chronic pain. Unfortunately, the evidence for the effect of different anaestetic and analgesic regimens on chronic pain after surgery is confused. Several studies show benefit from regional anaestesia, for example, after hysterectomy, Caesarean section, iliac crest bone harvesting, and thoractomy. There are also studies, however, that have not shown benefit. Several studies have looked at multimodal analgesic techniques and the use of drugs such as gabapentin, venlafaxine, and ketamine, but once again the results are not consistent (cf. W. A. Macrae, British Journal of Anaethesia 2008, 101(1), 77-86).
It is known that conventional opioid analgesics can detrimentally influence the development of chronic pain. For example, L. DeYoung et al., Molecular Pain, 2008, 4(7), 1-12 report that morphine does not inhibit incision-induced hyperalgesia in mice hindpaw 24 h after incision, i.e. surgery. While in mice treated with brine hyperalgesia decreases 72 h after incision, hyperalgesia is even maintained in mice treated with morphine. Thus, as far as the inhibition of postoperative hyperalgesia in mice is concerned, morphine does have no advantageous effect or even is disadvantageous.
There is a demand for medicaments that are useful for treating or inhibiting the chronification of pain and that are useful for treating pain in subjects suffering from chronification of pain.
Neuropathic pain is a major problem for clinicians, as available treatments produce incomplete pain relief, and have dose-limiting side effects. Besides, neuropathic pain in territories innervated by the trigeminal system (“cephalic” territories) is even more difficult to treat than that in other parts of the body (“extracephalic” territories). Indeed, neuropathic pain symptoms in cephalic versus extracephalic territory are differentially attenuated by drugs. Previous investigations in rat models of chronic constriction injury to the sciatic nerve (CCI-SN) or the infraorbital nerve (CCI-ION) showed that morphine at low dose, tricyclic antidepressants and tetrodotoxin reversed allodynia/hyperalgesia in the hindpaw in CCI-SN rats but were inactive against allodynia in the vibrissae territory in CCI-ION rats.
Conversely, anti-migraine drugs such as triptans and CGRP receptor antagonists significantly reduced allodynia in CCI-ION rats but were inactive in CCI-SN rats. Further investigations also showed that physiopathological mechanisms underlying neuropathic pain differed in CCI-SN vs CCI-ION rats. In particular, CCI-SN was found to trigger interleukin-6 (IL-6) production in the ipsilateral dorsal horn of the lumbar spinal cord whereas no IL-6 induction could be detected in the spinal nucleus of the trigeminal nerve (Sp5c) in CCI-ION rats.
A potential strategy for enhancing the efficacy of pharmacological treatments without causing further undesirable side effects can be the use of drug combinations. Notably, in CCI-ION rats, it has been demonstrated that the combined administration of the glycine/NMDA receptor antagonist (+)-HA966 and morphine attenuated cephalic neuropathic pain although each drug alone was inactive.
With regard to chronic pain, tapentadol has been shown to exert clear-cut antihyperalgesic/antiallodynic effects in rats suffering from neuropathic pain caused by streptozotocin administration (diabetic polyneuropathy), spinal nerve ligation or CCI-SN. However, all these models concerned neuropathic pain in extracephalic territories, and none is known yet regarding the potential antiallodynic/antihyperalgesic effects of tapentadol in cephalic territories.
There is a need for medicaments that are useful for treating or inhibiting migraine.